Cockayne syndrome (Year of the Zebra 2026) — Transcript

Cockayne Syndrome or CS is a rare genetic neurodegenerative condition resulting from defects in DNA repair.

And is characterized by distinct facial characteristics, disrupted growth, developmental delays, sunlight sensitivity, and premature aging.

CS is caused by mutations or pathogenic variants in either the ERCC8 or ERCC6 gene, which code for the CSA and CSB proteins respectively.

This is an autosomal recessive condition, meaning that to be affected, a child must inherit two faulty copies of the gene, one from each parent. The CSA and CSB proteins from these genes are involved in the identification and repair of damaged DNA, the genetic code found in each cell.

Everyone's DNA is routinely damaged by normal "wear and tear" in the human body over time, as well as by harmful radiation found in the environment, such as UV rays, X-rays, and gamma rays.

Usually, damaged DNA is repaired during a process called nucleotide excision repair or NER. In CS, faulty ERCC8 or ERCC6 genes produce proteins that cannot identify or remove damaged DNA. The damaged DNA then builds up and leads to cell dysfunction or cell death.

CSA and CSB proteins also do other "jobs" in cells, e.g. regulation of other proteins. Whether the symptoms found in individuals with CS are due to the loss of DNA repair functionality, these other jobs, or both, is the subject of ongoing research.

Although CS affects overall growth and development, individuals with CS are happy and outgoing. They are very social and love to be around people.

CS affects the eyes, ears, muscles, gastrointestinal system, and skin, and may reduce the ability to fight infection.

Affected individuals develop distinct facial features, such as sunken eyes, a slender nose, and prominent ears. Physical growth is disrupted, resulting in microcephaly or small head, and short stature.

Neurologic symptoms include intellectual disabilities, tremors, speech difficulties, dementia, and sometimes seizures.

Hearing loss and eye problems, such as cataracts and nystagmus, eye shaking, or involuntary horizontal eye movement are common. Patients may experience limited mobility due to muscle spasms or difficulty with walking.

Individuals living with CS have swallowing and digestive problems, metabolic dysfunction, and commonly are underweight. Even minimal exposure to sunlight can cause severe sunburns, and in some, it can cause redness and scaling skin around the eyes. Unlike related conditions, people with CS are not prone to getting skin cancer.

CS is suspected when a child has the characteristic facial features, developmental delay, sun sensitivity, and disrupted growth. MRI of the brain may show structural differences. Definitive diagnosis of CS is made when genetic testing finds two pathogenic variants in either the ERCC8 or ERCC6 genes.

CS is typically categorized into three main types, distinguished by the age of onset and severity of symptoms. Type 1 is the classic form; symptoms appear within the first two years of life. Type 2 is the most severe; symptoms are present at birth or within the first few months. Type 3 is a milder form, with symptoms appearing later in childhood or adolescence. Adult-onset CS has also been identified. While these categories provide a framework for understanding CS, it's crucial to remember that each individual's presentation and progression is unique.

The treatment of CS is mainly supportive. Early intervention with supplemental nutrition and therapies, including physical, occupational, speech, and vision therapy, can improve quality of life for individuals living with CS.

Gastrointestinal support is critical for growth and strength, and should focus on delivering calorie-rich nutrition using supplements. When needed, gastrointestinal tube feedings or intravenous feedings can support an individual with CS to achieve adequate nutrition.

Sun protection should include wearing broad-brimmed hats, UV-resistant clothing, and sunscreen. Special glasses or a UV-filtering mask can be worn to protect the eyes.

Regular eye examinations and surgical cataract removal can help preserve vision. Hearing loss can be managed with hearing aids or cochlear implants.

Medications can be used to reduce muscle spasms and tremors and prevent seizures. Certain medications, such as the antibiotic metronidazole, must be avoided because they can cause liver damage and death. Once diagnosed with CS, metronidazole should be listed as a 'drug to be avoided' in the individual's electronic medical record.

Assistive mobility devices, such as walkers and wheelchairs, can improve an individual's independence and involvement in social and educational activities.

Socio-educational and psychological support is important for affected individuals and their families. Genetic counseling is recommended for biological parents of children with CS to help with future family planning decisions.

In summary, CS is a rare genetic condition resulting from pathogenic variants of the ERCC8 or ERCC6 gene that lead to inadequate repair of DNA damage. CS is characterized by unique facial characteristics, disrupted growth, developmental delays, sunlight sensitivity, degeneration of the brain and spinal cord, and signs of premature aging.

Diagnosis is confirmed by genetic testing, and treatment focuses on symptom management. Early intervention with supplemental nutrition and specialized therapies can improve quality of life for affected individuals. Ongoing research is focused on better understanding the causes of CS at the molecular level and developing more effective treatments for individuals with CS.